STAT6 C-terminal; This family represents the C-terminus of mammalian STAT6 (Signal transducer and activator of transcription 6), it contains an LXXLL motif which binds to NCOA1 (Nuclear receptor coactivator 1).

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 341942077  655 PLPTPEPQMPAMVPPYDLGMAPDAS--MQLSSDM---GYPP--QSIHSFQ--SLEESMSVLPSFQEPHLQMPPNMSQITM 725
Cdd:pfam14596   1 PLPTPEPQMPAMVPSYDLGMASDSSmnMQLGSDMvsqVYPPpsHSIPSYQalPLEESVNVLTAFQEPHLQMPPSLNQMNL 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 341942077  726 PFDQPHPQGLLQCQSQEHAVSSPEPMLCSDVTMVEDSCLTQPVGGFPQGTWVSEDMYPPLMPPTEQDLTKLLLENQGEA- 804
Cdd:pfam14596  81 SFDQPHPQGLLPCQPQEHAVSSPEPLLCSDVTMAEDSCLSQQVGGFPQGTWVGEDMFPPLLPPTEQDLTKLLLEGQGEAg 160

                         170       180       190
                  ....*....|....*....|....*....|...
gi 341942077  805 GGSLGSQPLLQPSPYGQSGISLSHLDLRTNPSW 837
Cdd:pfam14596 161 GGSLGVQPLLQPSHYGQSGISMSHLDLRANPSW 193

Src homology 2 (SH2) domain found in signal transducer and activator of transcription (STAT) 6 proteins; STAT6 mediate signals from the IL-4 receptor. Unlike the other STAT proteins which bind an IFNgamma Activating Sequence (GAS), STAT6 stands out as having a unique binding site preference. This site consists of a palindromic sequence separated by a 3 bp spacer (TTCNNNG-AA)(N3 site). STAT6 is able to bind the GAS site but only at a low affinity. STAT6 may be an important regulator of mitogenesis when cells respond normally to IL-4. There is speculation that the inappropriate activation of STAT6 is involved in uncontrolled cell growth in an oncogenic state. IFNgamma is a negative regulator of STAT6 dependent transcription of target genes. Bcl-6 is another negative regulator of STAT6 activity. Bcl-6 is a transcriptional repressor normally expressed in germinal center B cells and some T cells. IL-4 signaling via STAT6 initially occurs unopposed, but is then dampened by a negative feedback mechanism through the IL-4/Stat6 dependent induction of SOCS1 expression. The IL-4 dependent aspect of Th2 differentiation requires the activation of STAT6. IL-4 signaling and STAT6 appear to play an important role in the immune response. Recently, it was shown that large scale chromatin remodeling of the IL-4 gene occurs as cells differentiate into Th2 effectors is STAT6 dependent. STAT proteins mediate the signaling of cytokines and a number of growth factors from the receptors of these extracellular signaling molecules to the cell nucleus. STATs are specifically phosphorylated by receptor-associated Janus kinases, receptor tyrosine kinases, or cytoplasmic tyrosine kinases. The phosphorylated STAT molecules dimerize by reciprocal binding of their SH2 domains to the phosphotyrosine residues. These dimeric STATs translocate into the nucleus, bind to specific DNA sequences, and regulate the transcription of their target genes. However there are a number of unphosphorylated STATs that travel between the cytoplasm and nucleus and some STATs that exist as dimers in unstimulated cells that can exert biological functions independent of being activated. There are seven mammalian STAT family members which have been identified: STAT1, STAT2, STAT3, STAT4, STAT5 (STAT5A and STAT5B), and STAT6. There are 6 conserved domains in STAT: N-terminal domain (NTD), coiled-coil domain (CCD), DNA-binding domain (DBD), alpha-helical linker domain (LD), SH2 domain, and transactivation domain (TAD). NTD is involved in dimerization of unphosphorylated STATs monomers and for the tetramerization between STAT1, STAT3, STAT4 and STAT5 on promoters with two or more tandem STAT binding sites. It also plays a role in promoting interactions with transcriptional co-activators such as CREB binding protein (CBP)/p300, as well as being important for nuclear import and deactivation of STATs involving tyrosine de-phosphorylation. CCD interacts with other proteins, such as IFN regulatory protein 9 (IRF-9/p48) with STAT1 and c-JUN with STAT3 and is also thought to participate in the negative regulation of these proteins. Distinct genes are bound to STATs via their DBD domain. This domain is also involved in nuclear translocation of activated STAT1 and STAT3 phosphorylated dimers upon cytokine stimulation. LD links the DNA-binding and SH2 domains and is important for the transcriptional activation of STAT1 in response to IFN-gamma. It also plays a role in protein-protein interactions and has also been implicated in the constitutive nucleocytoplasmic shuttling of unphosphorylated STATs in resting cells. The SH2 domain is necessary for receptor association and tyrosine phosphodimer formation. Residues within this domain may be particularly important for some cellular functions mediated by the STATs as well as residues adjacent to this domain. The TAD interacts with several proteins, namely minichromosome maintenance complex component 5 (MCM5), breast cancer 1 (BRCA1) and CBP/p300. TAD also contains a modulatory phosphorylation site that regulates STAT activity and is necessary for maximal transcription of a number of target genes. The conserved tyrosine residue present in the C-terminus is crucial for dimerization via interaction with the SH2 domain upon the interaction of the ligand with the receptor. STAT activation by tyrosine phosphorylation also determines nuclear import and retention, DNA binding to specific DNA elements in the promoters of responsive genes, and transcriptional activation of STAT dimers. In addition to the SH2 domain there is a coiled-coil domain, a DNA binding domain, and a transactivation domain in the STAT proteins. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 341942077 517 WFDGVLDLTKRCLRSYWSDRLIIGFISKQYVTSLLLNEPDGTFLLRFSDSEIGGITIAHVIRGQDGSSQIENIQPFSAKD 596
Cdd:cd10377    1 WFDGVLDLTKRCLRSYWSDRLIIGFISKQYVTSLLLNEPDGTFLLRFSDSEIGGITIAHVIRGQDGSPQIENIQPFSAKD 80

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|
gi 341942077 597 LSIRSLGDRIRDLAQLKNLYPKKPKDEAFRSHYKPEQMgKDGRGYVSTTI 646
Cdd:cd10377   81 LSIRSLGDRIRDLAQLKNLYPKKPKDEAFRSHYKPEQM-KDGRGYVPATI 129

STAT protein, protein interaction domain; STAT proteins (Signal Transducers and Activators of Transcription) are a family of transcription factors that are specifically activated to regulate gene transcription when cells encounter cytokines and growth factors. STAT proteins also include an SH2 domain pfam00017.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 341942077     2 SLWG----LISKMsPEKLQRLYVD-FPQRLRHLLADWLESQPWEFLVGSDAFCYNMASALLSATVQRLQATAGEQ-GKGN 75
Cdd:smart00964   1 SQWAqlqqLDSKF-LEQVQQLYGDnFPMELRHYLADWIESQDWELAANDEAQATRLFHNLLEQLDQQLSRFSQESnFLLK 79

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|.
gi 341942077    76 SILPHI-STLESIYQRDPLKLVATIRQILQGEKKAVIEEFR 115
Cdd:smart00964  80 HNLRHIkSNLQSLYQENPLELARIIRNILQEERRILAEASR 120

STAT6 C-terminal; This family represents the C-terminus of mammalian STAT6 (Signal transducer and activator of transcription 6), it contains an LXXLL motif which binds to NCOA1 (Nuclear receptor coactivator 1).

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 341942077  655 PLPTPEPQMPAMVPPYDLGMAPDAS--MQLSSDM---GYPP--QSIHSFQ--SLEESMSVLPSFQEPHLQMPPNMSQITM 725
Cdd:pfam14596   1 PLPTPEPQMPAMVPSYDLGMASDSSmnMQLGSDMvsqVYPPpsHSIPSYQalPLEESVNVLTAFQEPHLQMPPSLNQMNL 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 341942077  726 PFDQPHPQGLLQCQSQEHAVSSPEPMLCSDVTMVEDSCLTQPVGGFPQGTWVSEDMYPPLMPPTEQDLTKLLLENQGEA- 804
Cdd:pfam14596  81 SFDQPHPQGLLPCQPQEHAVSSPEPLLCSDVTMAEDSCLSQQVGGFPQGTWVGEDMFPPLLPPTEQDLTKLLLEGQGEAg 160

                         170       180       190
                  ....*....|....*....|....*....|...
gi 341942077  805 GGSLGSQPLLQPSPYGQSGISLSHLDLRTNPSW 837
Cdd:pfam14596 161 GGSLGVQPLLQPSHYGQSGISMSHLDLRANPSW 193

Src homology 2 (SH2) domain found in signal transducer and activator of transcription (STAT) 6 proteins; STAT6 mediate signals from the IL-4 receptor. Unlike the other STAT proteins which bind an IFNgamma Activating Sequence (GAS), STAT6 stands out as having a unique binding site preference. This site consists of a palindromic sequence separated by a 3 bp spacer (TTCNNNG-AA)(N3 site). STAT6 is able to bind the GAS site but only at a low affinity. STAT6 may be an important regulator of mitogenesis when cells respond normally to IL-4. There is speculation that the inappropriate activation of STAT6 is involved in uncontrolled cell growth in an oncogenic state. IFNgamma is a negative regulator of STAT6 dependent transcription of target genes. Bcl-6 is another negative regulator of STAT6 activity. Bcl-6 is a transcriptional repressor normally expressed in germinal center B cells and some T cells. IL-4 signaling via STAT6 initially occurs unopposed, but is then dampened by a negative feedback mechanism through the IL-4/Stat6 dependent induction of SOCS1 expression. The IL-4 dependent aspect of Th2 differentiation requires the activation of STAT6. IL-4 signaling and STAT6 appear to play an important role in the immune response. Recently, it was shown that large scale chromatin remodeling of the IL-4 gene occurs as cells differentiate into Th2 effectors is STAT6 dependent. STAT proteins mediate the signaling of cytokines and a number of growth factors from the receptors of these extracellular signaling molecules to the cell nucleus. STATs are specifically phosphorylated by receptor-associated Janus kinases, receptor tyrosine kinases, or cytoplasmic tyrosine kinases. The phosphorylated STAT molecules dimerize by reciprocal binding of their SH2 domains to the phosphotyrosine residues. These dimeric STATs translocate into the nucleus, bind to specific DNA sequences, and regulate the transcription of their target genes. However there are a number of unphosphorylated STATs that travel between the cytoplasm and nucleus and some STATs that exist as dimers in unstimulated cells that can exert biological functions independent of being activated. There are seven mammalian STAT family members which have been identified: STAT1, STAT2, STAT3, STAT4, STAT5 (STAT5A and STAT5B), and STAT6. There are 6 conserved domains in STAT: N-terminal domain (NTD), coiled-coil domain (CCD), DNA-binding domain (DBD), alpha-helical linker domain (LD), SH2 domain, and transactivation domain (TAD). NTD is involved in dimerization of unphosphorylated STATs monomers and for the tetramerization between STAT1, STAT3, STAT4 and STAT5 on promoters with two or more tandem STAT binding sites. It also plays a role in promoting interactions with transcriptional co-activators such as CREB binding protein (CBP)/p300, as well as being important for nuclear import and deactivation of STATs involving tyrosine de-phosphorylation. CCD interacts with other proteins, such as IFN regulatory protein 9 (IRF-9/p48) with STAT1 and c-JUN with STAT3 and is also thought to participate in the negative regulation of these proteins. Distinct genes are bound to STATs via their DBD domain. This domain is also involved in nuclear translocation of activated STAT1 and STAT3 phosphorylated dimers upon cytokine stimulation. LD links the DNA-binding and SH2 domains and is important for the transcriptional activation of STAT1 in response to IFN-gamma. It also plays a role in protein-protein interactions and has also been implicated in the constitutive nucleocytoplasmic shuttling of unphosphorylated STATs in resting cells. The SH2 domain is necessary for receptor association and tyrosine phosphodimer formation. Residues within this domain may be particularly important for some cellular functions mediated by the STATs as well as residues adjacent to this domain. The TAD interacts with several proteins, namely minichromosome maintenance complex component 5 (MCM5), breast cancer 1 (BRCA1) and CBP/p300. TAD also contains a modulatory phosphorylation site that regulates STAT activity and is necessary for maximal transcription of a number of target genes. The conserved tyrosine residue present in the C-terminus is crucial for dimerization via interaction with the SH2 domain upon the interaction of the ligand with the receptor. STAT activation by tyrosine phosphorylation also determines nuclear import and retention, DNA binding to specific DNA elements in the promoters of responsive genes, and transcriptional activation of STAT dimers. In addition to the SH2 domain there is a coiled-coil domain, a DNA binding domain, and a transactivation domain in the STAT proteins. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 341942077 517 WFDGVLDLTKRCLRSYWSDRLIIGFISKQYVTSLLLNEPDGTFLLRFSDSEIGGITIAHVIRGQDGSSQIENIQPFSAKD 596
Cdd:cd10377    1 WFDGVLDLTKRCLRSYWSDRLIIGFISKQYVTSLLLNEPDGTFLLRFSDSEIGGITIAHVIRGQDGSPQIENIQPFSAKD 80

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|
gi 341942077 597 LSIRSLGDRIRDLAQLKNLYPKKPKDEAFRSHYKPEQMgKDGRGYVSTTI 646
Cdd:cd10377   81 LSIRSLGDRIRDLAQLKNLYPKKPKDEAFRSHYKPEQM-KDGRGYVPATI 129

STAT protein, DNA binding domain; STAT proteins (Signal Transducers and Activators of Transcription) are a family of transcription factors that are specifically activated to regulate gene transcription when cells encounter cytokines and growth factors. This family represents the DNA binding domain of STAT, which has an ig-like fold. STAT proteins also include an SH2 domain pfam00017.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 341942077  277 KQPPQVLKTQTKFQAGVRFLLGLQFlgTSAKPPMVRADMVTEKQARELSLAQGpGTGVESTGEIMNNTVPLENSIPSNCC 356
Cdd:pfam02864   1 KQPPQVLKTNTKFSVTVRLLVGLPL--NIELNPQVKVKIVSEKQARELQQIKG-FRKFNISGEILNNKALLEYESQNGGL 77

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 341942077  357 SALFKNLLLKKIKRCERKGTESVTEEKCAVLFSTSFTLGpnKLLIQLQALSLPLVVI 413
Cdd:pfam02864  78 SAEFRNLSLKEIKRGERKGSLSVTEEKFALLFETQFTLG--GLVFDLWTLSLPVVVI 132

STAT protein, protein interaction domain; STAT proteins (Signal Transducers and Activators of Transcription) are a family of transcription factors that are specifically activated to regulate gene transcription when cells encounter cytokines and growth factors. STAT proteins also include an SH2 domain pfam00017.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 341942077    2 SLWGLISKMSPEKLQR---LYVD-FPQRLRHLLADWLESQPWEFLVGSDAFCYNMASALLSATVQRLQATAGEQGK--GN 75
Cdd:pfam02865   1 SLWAQLQQLDGEALEQvqqLYGDhFPIEVRHYLAQWIESQDWEDAAQDESLATVLFHALLSELDSQASRFVQEDNFllKH 80

                          90       100       110
                  ....*....|....*....|....*....|....*..
gi 341942077   76 SILPHISTLESIYQRDPLKLVATIRQILQGEKKAVIE 112
Cdd:pfam02865  81 KLREIAKNLQSRYQENPLELARIIRNCLREERRILQE 117

Src homology 2 domains; Src homology 2 domains bind phosphotyrosine-containing polypeptides via 2 surface pockets. Specificity is provided via interaction with residues that are distinct from the phosphotyrosine. Only a single occurrence of a SH2 domain has been found in S. cerevisiae.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 341942077   540 GFISKQYVTSLLLNEPDGTFLLRFSDSEIGGITIAHVIRGqdgssQIENIQPFSAKDlSIRSLGDRIR--DLAQLKNLYP 617
Cdd:smart00252   6 GFISREEAEKLLKNEGDGDFLVRDSESSPGDYVLSVRVKG-----KVKHYRIRRNED-GKFYLEGGRKfpSLVELVEHYQ 79

                   ...
gi 341942077   618 KKP 620
Cdd:smart00252  80 KNS 82

STAT6 C-terminal; This family represents the C-terminus of mammalian STAT6 (Signal transducer and activator of transcription 6), it contains an LXXLL motif which binds to NCOA1 (Nuclear receptor coactivator 1).

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 341942077  655 PLPTPEPQMPAMVPPYDLGMAPDAS--MQLSSDM---GYPP--QSIHSFQ--SLEESMSVLPSFQEPHLQMPPNMSQITM 725
Cdd:pfam14596   1 PLPTPEPQMPAMVPSYDLGMASDSSmnMQLGSDMvsqVYPPpsHSIPSYQalPLEESVNVLTAFQEPHLQMPPSLNQMNL 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 341942077  726 PFDQPHPQGLLQCQSQEHAVSSPEPMLCSDVTMVEDSCLTQPVGGFPQGTWVSEDMYPPLMPPTEQDLTKLLLENQGEA- 804
Cdd:pfam14596  81 SFDQPHPQGLLPCQPQEHAVSSPEPLLCSDVTMAEDSCLSQQVGGFPQGTWVGEDMFPPLLPPTEQDLTKLLLEGQGEAg 160

                         170       180       190
                  ....*....|....*....|....*....|...
gi 341942077  805 GGSLGSQPLLQPSPYGQSGISLSHLDLRTNPSW 837
Cdd:pfam14596 161 GGSLGVQPLLQPSHYGQSGISMSHLDLRANPSW 193

Src homology 2 (SH2) domain found in signal transducer and activator of transcription (STAT) 6 proteins; STAT6 mediate signals from the IL-4 receptor. Unlike the other STAT proteins which bind an IFNgamma Activating Sequence (GAS), STAT6 stands out as having a unique binding site preference. This site consists of a palindromic sequence separated by a 3 bp spacer (TTCNNNG-AA)(N3 site). STAT6 is able to bind the GAS site but only at a low affinity. STAT6 may be an important regulator of mitogenesis when cells respond normally to IL-4. There is speculation that the inappropriate activation of STAT6 is involved in uncontrolled cell growth in an oncogenic state. IFNgamma is a negative regulator of STAT6 dependent transcription of target genes. Bcl-6 is another negative regulator of STAT6 activity. Bcl-6 is a transcriptional repressor normally expressed in germinal center B cells and some T cells. IL-4 signaling via STAT6 initially occurs unopposed, but is then dampened by a negative feedback mechanism through the IL-4/Stat6 dependent induction of SOCS1 expression. The IL-4 dependent aspect of Th2 differentiation requires the activation of STAT6. IL-4 signaling and STAT6 appear to play an important role in the immune response. Recently, it was shown that large scale chromatin remodeling of the IL-4 gene occurs as cells differentiate into Th2 effectors is STAT6 dependent. STAT proteins mediate the signaling of cytokines and a number of growth factors from the receptors of these extracellular signaling molecules to the cell nucleus. STATs are specifically phosphorylated by receptor-associated Janus kinases, receptor tyrosine kinases, or cytoplasmic tyrosine kinases. The phosphorylated STAT molecules dimerize by reciprocal binding of their SH2 domains to the phosphotyrosine residues. These dimeric STATs translocate into the nucleus, bind to specific DNA sequences, and regulate the transcription of their target genes. However there are a number of unphosphorylated STATs that travel between the cytoplasm and nucleus and some STATs that exist as dimers in unstimulated cells that can exert biological functions independent of being activated. There are seven mammalian STAT family members which have been identified: STAT1, STAT2, STAT3, STAT4, STAT5 (STAT5A and STAT5B), and STAT6. There are 6 conserved domains in STAT: N-terminal domain (NTD), coiled-coil domain (CCD), DNA-binding domain (DBD), alpha-helical linker domain (LD), SH2 domain, and transactivation domain (TAD). NTD is involved in dimerization of unphosphorylated STATs monomers and for the tetramerization between STAT1, STAT3, STAT4 and STAT5 on promoters with two or more tandem STAT binding sites. It also plays a role in promoting interactions with transcriptional co-activators such as CREB binding protein (CBP)/p300, as well as being important for nuclear import and deactivation of STATs involving tyrosine de-phosphorylation. CCD interacts with other proteins, such as IFN regulatory protein 9 (IRF-9/p48) with STAT1 and c-JUN with STAT3 and is also thought to participate in the negative regulation of these proteins. Distinct genes are bound to STATs via their DBD domain. This domain is also involved in nuclear translocation of activated STAT1 and STAT3 phosphorylated dimers upon cytokine stimulation. LD links the DNA-binding and SH2 domains and is important for the transcriptional activation of STAT1 in response to IFN-gamma. It also plays a role in protein-protein interactions and has also been implicated in the constitutive nucleocytoplasmic shuttling of unphosphorylated STATs in resting cells. The SH2 domain is necessary for receptor association and tyrosine phosphodimer formation. Residues within this domain may be particularly important for some cellular functions mediated by the STATs as well as residues adjacent to this domain. The TAD interacts with several proteins, namely minichromosome maintenance complex component 5 (MCM5), breast cancer 1 (BRCA1) and CBP/p300. TAD also contains a modulatory phosphorylation site that regulates STAT activity and is necessary for maximal transcription of a number of target genes. The conserved tyrosine residue present in the C-terminus is crucial for dimerization via interaction with the SH2 domain upon the interaction of the ligand with the receptor. STAT activation by tyrosine phosphorylation also determines nuclear import and retention, DNA binding to specific DNA elements in the promoters of responsive genes, and transcriptional activation of STAT dimers. In addition to the SH2 domain there is a coiled-coil domain, a DNA binding domain, and a transactivation domain in the STAT proteins. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 341942077 517 WFDGVLDLTKRCLRSYWSDRLIIGFISKQYVTSLLLNEPDGTFLLRFSDSEIGGITIAHVIRGQDGSSQIENIQPFSAKD 596
Cdd:cd10377    1 WFDGVLDLTKRCLRSYWSDRLIIGFISKQYVTSLLLNEPDGTFLLRFSDSEIGGITIAHVIRGQDGSPQIENIQPFSAKD 80

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|
gi 341942077 597 LSIRSLGDRIRDLAQLKNLYPKKPKDEAFRSHYKPEQMgKDGRGYVSTTI 646
Cdd:cd10377   81 LSIRSLGDRIRDLAQLKNLYPKKPKDEAFRSHYKPEQM-KDGRGYVPATI 129

Coiled-coil domain of Signal Transducer and Activator of Transcription 6 (STAT6); This family consists of the coiled-coil (alpha) domain of the STAT6 proteins (Signal Transducer and Activator of Transcription 6, or Signal Transduction And Transcription 6). SImilar to STAT3 and STAT5. the coiled-coil domain (CCD) of STAT6 is required for constitutive nuclear localization signals (NLS) function; small deletions within the CCD can abrogate nuclear import. Studies show that the CCD binds to the importin-alpha3 NLS adapter in most cells.STAT6 is essential for the functional responses of T helper 2 (Th2) lymphocyte mediated by interleukins IL-4 and IL-13. STAT6 almost exclusively mediates the expression of genes activated by these cytokines; IL-4 signaling regulates the expression of genes involved in immune and anti-inflammatory responses. Abnormal production of IL-4 and IL-13 play important roles in the pathogenesis of asthma where upregulation of the Th2 response mediated by IL-4/IL-13 is a main characteristic. STAT6 has a unique extended transactivation domain, not found in other STATs, through which it recruits p300/CBP and NCoA-1, two coactivators needed for transcriptional activation by IL-4. STAT6 activation is linked to Kaposi's sarcoma-associated herpesvirus (KSHV)-associated cancers such as primary effusion lymphoma, a cancerous proliferation of B cells. Studies show that Meningeal solitary fibrous tumor (SFT) and hemangiopericytoma (HPC) represent a histopathologic spectrum linked by STAT6 nuclear expression and recurrent somatic fusions of the two genes, NGFI-A-binding protein 2 (NAB2) and STAT6 (NAB2-STAT6), similar to their soft tissue counterparts. It is associated with local recurrence and late distance metastasis of brain tumors to extracranial sites.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 341942077 105 GEKKAVIEEFRHLPGPFHRKQEELKFTTALGRLQHRVRETRLLRESLQQGAKTGQVSLQnlidpPVNGPGPSEDLATMLQ 184
Cdd:cd16856    1 GEKAAVLLRPQHLPLSIHQLQEELKFDVENLELQHRVGQIHRLQLSLQQEKKSERIQQQ-----EANGTSPLQERAQLLQ 75

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 341942077 185 GTVGDLEATQALVLKRIQIWKRQQQLAGNGTPFEESLAGLQERCESLVEIYSQLQQEIGAASGELEPKTRASLISRLDEV 264
Cdd:cd16856   76 EAVGELEQAQSQVLKRIQIWKRQQQLAGNGAPFDENLSPLQTRCEQLVDVNFQLRQEVMLAGGELGSELLSTLQERLNSL 155

                        170
                 ....*....|..
gi 341942077 265 LRTLVTSSFLVE 276
Cdd:cd16856  156 LQTLIQSSLVVE 167

DNA-binding domain of Signal Transducer and Activator of Transcription 5 (STAT5); This family consists of the DNA-binding domain (DBD) of the STAT5 proteins (Signal Transducer and Activator of Transcription 5, or Signal Transduction And Transcription 4), which include STAT5A and STAT5B, both of which are >90% identical despite being encoded by separate genes. The DNA binding domain has an Ig-like fold. STAT5A and STAT5B regulate erythropoiesis, lymphopoiesis, and the maintenance of the hematopoietic stem cell population. STAT5A and STAT5B have overlapping and redundant functions; both isoforms can be activated by the same set of cytokines, but some cytokines preferentially activate either STAT5A or STAT5B, e.g. during pregnancy and lactation, STAT5A rather than STAT5B is required for the production of luminal progenitor cells from mammary stem cells and is essential for the differentiation of milk producing alveolar cells during pregnancy. STAT5 has been found to be constitutively phosphorylated in cancer cells, and therefore constantly activated, either by aberrant cell signaling expression or by mutations. It differentially regulates cellular behavior in human mammary carcinoma. Prolactin (PRL) in the prostate gland can induce growth and survival of prostate cancer cells and tissues through the activation of STAT5, its downstream target; PRL expression and STAT5 activation correlates with disease severity. STAT5A and STAT5B are central signaling molecules in leukemias driven by Abelson fusion tyrosine kinases, displaying unique nuclear shuttling mechanisms and having a key role in resistance of leukemic cells against treatment with tyrosine kinase inhibitors (TKI). In addition, STAT5A and STAT5B promote survival of leukemic stem cells. STAT5 is a key transcription factor for IL-3-mediated inhibition of RANKL-induced osteoclastogenesis via the induction of the expression of Id genes. Autosomal recessive STAT5B mutations are associated with severe growth failure, insulin-like growth factor (IGF) deficiency and growth hormone insensitivity (GHI) syndrome. STAT5B deficiency can lead to potentially fatal primary immunodeficiency.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 341942077 273 FLVEKQPPQVLKTQTKFQAGVRFLLGLQfLGTSAKPPMVRADMVTEKQARELsLAQGPGTGVESTGEIMNNTVPLENSIP 352
Cdd:cd16849    1 FIIEKQPPQVLKTQTRFAATVRLLVGGK-LNVHMNPPQVKATIISEQQAKAL-LKNENITRNETSGEILNNCGVMEYHQA 78

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 341942077 353 SNCCSALFKNLLLKKIKRCERKGTESVTEEKCAVLFSTSFTLGPNKLLIQLQALSLPLVVIVHGNQDNNAKATILWDNAF 432
Cdd:cd16849   79 TGQLSVSFRNMSLKRIKRADKRGAESVTEEKFTILFQSQFSVGGNELVFQVWTLSLPVVVIVHGNQESNATATVLWDNAF 158

                 .
gi 341942077 433 S 433
Cdd:cd16849  159 A 159

Src homology 2 (SH2) domain found in signal transducer and activator of transcription (STAT) 5 proteins; STAT5 is a member of the STAT family of transcription factors. Two highly related proteins, STAT5a and STAT5b are encoded by separate genes, but are 90% identical at the amino acid level. Both STAT5a and STAT5b are ubiquitously expressed and functionally interchangeable. Mice lacking either STAT5a or STAT5b have mild defects in prolactin dependent mammary differentiation or sexually dimorphic growth hormone-dependent effects, respectively. Mice lacking both STAT5a and STAT5b exhibit a perinatal lethal phenotype and have multiple defects, including anemia and a virtual absence of B and T lymphocytes. STAT proteins mediate the signaling of cytokines and a number of growth factors from the receptors of these extracellular signaling molecules to the cell nucleus. STATs are specifically phosphorylated by receptor-associated Janus kinases, receptor tyrosine kinases, or cytoplasmic tyrosine kinases. The phosphorylated STAT molecules dimerize by reciprocal binding of their SH2 domains to the phosphotyrosine residues. These dimeric STATs translocate into the nucleus, bind to specific DNA sequences, and regulate the transcription of their target genes. However there are a number of unphosphorylated STATs that travel between the cytoplasm and nucleus and some STATs that exist as dimers in unstimulated cells that can exert biological functions independent of being activated. There are seven mammalian STAT family members which have been identified: STAT1, STAT2, STAT3, STAT4, STAT5 (STAT5A and STAT5B), and STAT6. There are 6 conserved domains in STAT: N-terminal domain (NTD), coiled-coil domain (CCD), DNA-binding domain (DBD), alpha-helical linker domain (LD), SH2 domain, and transactivation domain (TAD). NTD is involved in dimerization of unphosphorylated STATs monomers and for the tetramerization between STAT1, STAT3, STAT4 and STAT5 on promoters with two or more tandem STAT binding sites. It also plays a role in promoting interactions with transcriptional co-activators such as CREB binding protein (CBP)/p300, as well as being important for nuclear import and deactivation of STATs involving tyrosine de-phosphorylation. CCD interacts with other proteins, such as IFN regulatory protein 9 (IRF-9/p48) with STAT1 and c-JUN with STAT3 and is also thought to participate in the negative regulation of these proteins. Distinct genes are bound to STATs via their DBD domain. This domain is also involved in nuclear translocation of activated STAT1 and STAT3 phosphorylated dimers upon cytokine stimulation. LD links the DNA-binding and SH2 domains and is important for the transcriptional activation of STAT1 in response to IFN-gamma. It also plays a role in protein-protein interactions and has also been implicated in the constitutive nucleocytoplasmic shuttling of unphosphorylated STATs in resting cells. The SH2 domain is necessary for receptor association and tyrosine phosphodimer formation. Residues within this domain may be particularly important for some cellular functions mediated by the STATs as well as residues adjacent to this domain. The TAD interacts with several proteins, namely minichromosome maintenance complex component 5 (MCM5), breast cancer 1 (BRCA1) and CBP/p300. TAD also contains a modulatory phosphorylation site that regulates STAT activity and is necessary for maximal transcription of a number of target genes. The conserved tyrosine residue present in the C-terminus is crucial for dimerization via interaction with the SH2 domain upon the interaction of the ligand with the receptor. STAT activation by tyrosine phosphorylation also determines nuclear import and retention, DNA binding to specific DNA elements in the promoters of responsive genes, and transcriptional activation of STAT dimers. In addition to the SH2 domain there is a coiled-coil domain, a DNA binding domain, and a transactivation domain in the STAT proteins.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 341942077 517 WFDGVLDLTKRCLRSYWSDRLIIGFISKQYVTSLLLNEPDGTFLLRFSDSEIGGITIAHVIRGQDgsSQIENIQPFSAKD 596
Cdd:cd10376    1 WFDGVMEVLKKHLKPHWNDGAILGFVNKQQAHDLLINKPDGTFLLRFSDSEIGGITIAWKFDSPD--RALWNLMPFTTRD 78

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 341942077 597 LSIRSLGDRIRDLAQLKNLYPKKPKDEAFRSHYKP---EQMGKDgrGYVSTTIKMTV 650
Cdd:cd10376   79 FSIRSLADRLGDLNYLIYVFPDRPKDEVFSKYYTPvlcNPSAVD--GYVKPQIKQVV 133

Src homology 2 (SH2) domain found in signal transducer and activator of transcription (STAT) 5b proteins; STAT5 is a member of the STAT family of transcription factors. Two highly related proteins, STAT5a and STAT5b are encoded by separate genes, but are 90% identical at the amino acid level. Both STAT5a and STAT5b are ubiquitously expressed and functionally interchangeable. Mice lacking either STAT5a or STAT5b have mild defects in prolactin dependent mammary differentiation or sexually dimorphic growth hormone-dependent effects, respectively. Mice lacking both STAT5a and STAT5b exhibit a perinatal lethal phenotype and have multiple defects, including anemia and a virtual absence of B and T lymphocytes. STAT proteins mediate the signaling of cytokines and a number of growth factors from the receptors of these extracellular signaling molecules to the cell nucleus. STATs are specifically phosphorylated by receptor-associated Janus kinases, receptor tyrosine kinases, or cytoplasmic tyrosine kinases. The phosphorylated STAT molecules dimerize by reciprocal binding of their SH2 domains to the phosphotyrosine residues. These dimeric STATs translocate into the nucleus, bind to specific DNA sequences, and regulate the transcription of their target genes. However there are a number of unphosphorylated STATs that travel between the cytoplasm and nucleus and some STATs that exist as dimers in unstimulated cells that can exert biological functions independent of being activated. There are seven mammalian STAT family members which have been identified: STAT1, STAT2, STAT3, STAT4, STAT5 (STAT5A and STAT5B), and STAT6. There are 6 conserved domains in STAT: N-terminal domain (NTD), coiled-coil domain (CCD), DNA-binding domain (DBD), alpha-helical linker domain (LD), SH2 domain, and transactivation domain (TAD). NTD is involved in dimerization of unphosphorylated STATs monomers and for the tetramerization between STAT1, STAT3, STAT4 and STAT5 on promoters with two or more tandem STAT binding sites. It also plays a role in promoting interactions with transcriptional co-activators such as CREB binding protein (CBP)/p300, as well as being important for nuclear import and deactivation of STATs involving tyrosine de-phosphorylation. CCD interacts with other proteins, such as IFN regulatory protein 9 (IRF-9/p48) with STAT1 and c-JUN with STAT3 and is also thought to participate in the negative regulation of these proteins. Distinct genes are bound to STATs via their DBD domain. This domain is also involved in nuclear translocation of activated STAT1 and STAT3 phosphorylated dimers upon cytokine stimulation. LD links the DNA-binding and SH2 domains and is important for the transcriptional activation of STAT1 in response to IFN-gamma. It also plays a role in protein-protein interactions and has also been implicated in the constitutive nucleocytoplasmic shuttling of unphosphorylated STATs in resting cells. The SH2 domain is necessary for receptor association and tyrosine phosphodimer formation. Residues within this domain may be particularly important for some cellular functions mediated by the STATs as well as residues adjacent to this domain. The TAD interacts with several proteins, namely minichromosome maintenance complex component 5 (MCM5), breast cancer 1 (BRCA1) and CBP/p300. TAD also contains a modulatory phosphorylation site that regulates STAT activity and is necessary for maximal transcription of a number of target genes. The conserved tyrosine residue present in the C-terminus is crucial for dimerization via interaction with the SH2 domain upon the interaction of the ligand with the receptor. STAT activation by tyrosine phosphorylation also determines nuclear import and retention, DNA binding to specific DNA elements in the promoters of responsive genes, and transcriptional activation of STAT dimers. In addition to the SH2 domain there is a coiled-coil domain, a DNA binding domain, and a transactivation domain in the STAT proteins. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 341942077 517 WFDGVLDLTKRCLRSYWSDRLIIGFISKQYVTSLLLNEPDGTFLLRFSDSEIGGITIAHVIRGQDgsSQIENIQPFSAKD 596
Cdd:cd10420    1 WFDGVMEVLKKHLKPHWNDGAILGFVNKQQAHDLLINKPDGTFLLRFSDSEIGGITIAWKFDSQE--RMFWNLMPFTTRD 78

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 341942077 597 LSIRSLGDRIRDLAQLKNLYPKKPKDEAFRSHYKP----EQMGKDGRGYVSTTIKMTV 650
Cdd:cd10420   79 FSIRSLADRLGDLNYLIYVFPDRPKDEVYSKYYTPvpcePATAKAVDGYVKPQIKQVV 136

Src homology 2 (SH2) domain found in signal transducer and activator of transcription (STAT) 3 proteins; STAT3 encoded by this gene is a member of the STAT protein family. STAT3 mediates the expression of a variety of genes in response to cell stimuli, and plays a key role in many cellular processes such as cell growth and apoptosis. The small GTPase Rac1 regulates the activity of STAT3 and PIAS3 inhibits it. Three alternatively spliced transcript variants encoding distinct isoforms have been described. STAT 3 activation is required for self-renewal of embryonic stem cells (ESCs) and is essential for the differentiation of the TH17 helper T cells. Mutations in the STAT3 gene result in Hyperimmunoglobulin E syndrome and human cancers. STAT3 has been shown to interact with Androgen receptor, C-jun, ELP2, EP300, Epidermal growth factor receptor, Glucocorticoid receptor, HIF1A, Janus kinase 1, KHDRBS1, Mammalian target of rapamycin, MyoD, NDUFA13, NFKB1, Nuclear receptor coactivator 1, Promyelocytic leukemia protein, RAC1, RELA, RET proto-oncogene, RPA2, Src, STAT1, and TRIP10. STAT proteins mediate the signaling of cytokines and a number of growth factors from the receptors of these extracellular signaling molecules to the cell nucleus. STATs are specifically phosphorylated by receptor-associated Janus kinases, receptor tyrosine kinases, or cytoplasmic tyrosine kinases. The phosphorylated STAT molecules dimerize by reciprocal binding of their SH2 domains to the phosphotyrosine residues. These dimeric STATs translocate into the nucleus, bind to specific DNA sequences, and regulate the transcription of their target genes. However there are a number of unphosphorylated STATs that travel between the cytoplasm and nucleus and some STATs that exist as dimers in unstimulated cells that can exert biological functions independent of being activated. There are seven mammalian STAT family members which have been identified: STAT1, STAT2, STAT3, STAT4, STAT5 (STAT5A and STAT5B), and STAT6. There are 6 conserved domains in STAT: N-terminal domain (NTD), coiled-coil domain (CCD), DNA-binding domain (DBD), alpha-helical linker domain (LD), SH2 domain, and transactivation domain (TAD). NTD is involved in dimerization of unphosphorylated STATs monomers and for the tetramerization between STAT1, STAT3, STAT4 and STAT5 on promoters with two or more tandem STAT binding sites. It also plays a role in promoting interactions with transcriptional co-activators such as CREB binding protein (CBP)/p300, as well as being important for nuclear import and deactivation of STATs involving tyrosine de-phosphorylation. CCD interacts with other proteins, such as IFN regulatory protein 9 (IRF-9/p48) with STAT1 and c-JUN with STAT3 and is also thought to participate in the negative regulation of these proteins. Distinct genes are bound to STATs via their DBD domain. This domain is also involved in nuclear translocation of activated STAT1 and STAT3 phosphorylated dimers upon cytokine stimulation. LD links the DNA-binding and SH2 domains and is important for the transcriptional activation of STAT1 in response to IFN-gamma. It also plays a role in protein-protein interactions and has also been implicated in the constitutive nucleocytoplasmic shuttling of unphosphorylated STATs in resting cells. The SH2 domain is necessary for receptor association and tyrosine phosphodimer formation. Residues within this domain may be particularly important for some cellular functions mediated by the STATs as well as residues adjacent to this domain. The TAD interacts with several proteins, namely minichromosome maintenance complex component 5 (MCM5), breast cancer 1 (BRCA1) and CBP/p300. TAD also contains a modulatory phosphorylation site that regulates STAT activity and is necessary for maximal transcription of a number of target genes. The conserved tyrosine residue present in the C-terminus is crucial for dimerization via interaction with the SH2 domain upon the interaction of the ligand with the receptor. STAT activation by tyrosine phosphorylation also determines nuclear import and retention, DNA binding to specific DNA elements in the promoters of responsive genes, and transcriptional activation of STAT dimers. In addition to the SH2 domain there is a coiled-coil domain, a DNA binding domain, and a transactivation domain in the STAT proteins. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 341942077 507 LLGRGFTFWQWFDGVLDLTKRCLRSYWSDRLIIGFISKQYVTSLLLNEPDGTFLLRFSD-SEIGGITIAHVIRGQDGSSQ 585
Cdd:cd10374    1 MAGKGFSFWVWLDNIIDLVKKYILALWNEGYIMGFISKERERAILSTKPPGTFLLRFSEsSKEGGVTFTWVEKDISGKTQ 80

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 341942077 586 IENIQPFSAKDLSIRS-----LGDRIRD-----LAQLKNLYPKKPKDEAFRSHYKPE 632
Cdd:cd10374   81 IQSVEPYTKQQLNNMSfaeiiMGYKIMDatnilVSPLVYLYPDIPKEEAFGKYCRPE 137

STAT protein, protein interaction domain; STAT proteins (Signal Transducers and Activators of Transcription) are a family of transcription factors that are specifically activated to regulate gene transcription when cells encounter cytokines and growth factors. STAT proteins also include an SH2 domain pfam00017.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 341942077    2 SLWGLISKMSPEKLQR---LYVD-FPQRLRHLLADWLESQPWEFLVGSDAFCYNMASALLSATVQRLQATAGEQGK--GN 75
Cdd:pfam02865   1 SLWAQLQQLDGEALEQvqqLYGDhFPIEVRHYLAQWIESQDWEDAAQDESLATVLFHALLSELDSQASRFVQEDNFllKH 80

                          90       100       110
                  ....*....|....*....|....*....|....*..
gi 341942077   76 SILPHISTLESIYQRDPLKLVATIRQILQGEKKAVIE 112
Cdd:pfam02865  81 KLREIAKNLQSRYQENPLELARIIRNCLREERRILQE 117

Src homology 2 (SH2) domain found in signal transducer and activator of transcription (STAT) 2 proteins; STAT2 is a member of the STAT protein family. In response to interferon, STAT2 forms a complex with STAT1 and IFN regulatory factor family protein p48 (ISGF3G), in which this protein acts as a transactivator, but lacks the ability to bind DNA directly. Transcription adaptor P300/CBP (EP300/CREBBP) has been shown to interact specifically with STAT2, which is thought to be involved in the process of blocking IFN-alpha response by adenovirus. STAT2 has been shown to interact with MED14, CREB-binding protein, SMARCA4, STAT1, IFNAR2, IFNAR1, and ISGF3G. STAT proteins mediate the signaling of cytokines and a number of growth factors from the receptors of these extracellular signaling molecules to the cell nucleus. STATs are specifically phosphorylated by receptor-associated Janus kinases, receptor tyrosine kinases, or cytoplasmic tyrosine kinases. The phosphorylated STAT molecules dimerize by reciprocal binding of their SH2 domains to the phosphotyrosine residues. These dimeric STATs translocate into the nucleus, bind to specific DNA sequences, and regulate the transcription of their target genes. However there are a number of unphosphorylated STATs that travel between the cytoplasm and nucleus and some STATs that exist as dimers in unstimulated cells that can exert biological functions independent of being activated. There are seven mammalian STAT family members which have been identified: STAT1, STAT2, STAT3, STAT4, STAT5 (STAT5A and STAT5B), and STAT6. There are 6 conserved domains in STAT: N-terminal domain (NTD), coiled-coil domain (CCD), DNA-binding domain (DBD), alpha-helical linker domain (LD), SH2 domain, and transactivation domain (TAD). NTD is involved in dimerization of unphosphorylated STATs monomers and for the tetramerization between STAT1, STAT3, STAT4 and STAT5 on promoters with two or more tandem STAT binding sites. It also plays a role in promoting interactions with transcriptional co-activators such as CREB binding protein (CBP)/p300, as well as being important for nuclear import and deactivation of STATs involving tyrosine de-phosphorylation. CCD interacts with other proteins, such as IFN regulatory protein 9 (IRF-9/p48) with STAT1 and c-JUN with STAT3 and is also thought to participate in the negative regulation of these proteins. Distinct genes are bound to STATs via their DBD domain. This domain is also involved in nuclear translocation of activated STAT1 and STAT3 phosphorylated dimers upon cytokine stimulation. LD links the DNA-binding and SH2 domains and is important for the transcriptional activation of STAT1 in response to IFN-gamma. It also plays a role in protein-protein interactions and has also been implicated in the constitutive nucleocytoplasmic shuttling of unphosphorylated STATs in resting cells. The SH2 domain is necessary for receptor association and tyrosine phosphodimer formation. Residues within this domain may be particularly important for some cellular functions mediated by the STATs as well as residues adjacent to this domain. The TAD interacts with several proteins, namely minichromosome maintenance complex component 5 (MCM5), breast cancer 1 (BRCA1) and CBP/p300. TAD also contains a modulatory phosphorylation site that regulates STAT activity and is necessary for maximal transcription of a number of target genes. The conserved tyrosine residue present in the C-terminus is crucial for dimerization via interaction with the SH2 domain upon the interaction of the ligand with the receptor. STAT activation by tyrosine phosphorylation also determines nuclear import and retention, DNA binding to specific DNA elements in the promoters of responsive genes, and transcriptional activation of STAT dimers. In addition to the SH2 domain there is a coiled-coil domain, a DNA binding domain, and a transactivation domain in the STAT proteins. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 341942077 517 WFDGVLDLTKRCLRSYWSDRLIIGFISKQYVTSLLLNEPDGTFLLRFSDSEIGGITIAHVIRGQDGSSQIENIQPFSAKD 596
Cdd:cd10373    1 WLDKILELVHDHLKDLWKDGRIMGFVSRNQERRLLKKTISGTFLLRFSETSEGGITCSWVEHQDDDKVLIYSVQPYTKEV 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....
gi 341942077 597 LSIRSLGDRIRD---LAQ-------LKNLYPKKPKDEAFRSHYK 630
Cdd:cd10373   81 LQSLPLTEIIRHyqlLTEenipenpLRFLYPRIPRDEAFGCYYQ 124

SH2 domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 341942077  538 IIGFISKQYVTSLLLNE-PDGTFLLRFSDSEIGGITIAHVIRGqdgssQIENIQPFSAKDL-SIRSLGDRIRDLAQLKNL 615
Cdd:pfam00017   2 YHGKISRQEAERLLLNGkPDGTFLVRESESTPGGYTLSVRDDG-----KVKHYKIQSTDNGgYYISGGVKFSSLAELVEH 76

                  .
gi 341942077  616 Y 616
Cdd:pfam00017  77 Y 77

DNA-binding domain of Signal Transducer and Activator of Transcription 1 (STAT1); This family consists of the DNA-binding domain (DBD) of the STAT1 proteins (Signal Transducer and Activator of Transcription 1, or Signal Transduction And Transcription 1). The DNA binding domain has an Ig-like fold. STAT1 plays an essential role in mediating responses to all types of interferons (IFN), transducing signals from cytoplasmic domains of transmembrane receptors into the nucleus where it regulates gene expression. Thus STAT1 is involved in modulating diverse cellular processes, such as antimicrobial activities, cell proliferation and cell death. STAT1 function is crucial in the innate and adaptive arm of immunity and protects from pathogen infections; phosphorylation of a critical tyrosine by Janus kinases (JAKs) leads to its activation and nuclear translocation, while phosphorylation of a critical serine is required for full transcriptional activation upon IFN stimulation and in response to cellular stress. Transcription of protein-encoding genes (including Stat1 itself) as well as expression of microRNAs (miRNAs) is regulated by activated STAT1. Animal studies have shown that STAT1 is generally considered a tumor suppressor but it can also act as a tumor promoter; its functions are not restricted to tumor cells, but extend to parts of the tumor microenvironment such as immune cells, endothelial cells. STAT1 abundance is a reliable marker for good prognosis in selected tumor types, but it can also correlate with disease progression. In head and neck cancer (HNC) patients, upregulation of STAT1-induced HLA class I enhances immunogenicity and clinical response to anti-EGFR mAb cetuximab therapy. In systemic juvenile idiopathic arthritis (sJIA) characterized by systemic inflammation and arthritis, STAT1 phosphorylation downstream of IFNs is impaired. It exerts anti-oncogenic activities through interferon-gamma and interferon-alpha. STAT1 may inhibit hepatocellular carcinoma cell growth by regulating p53-related cell cycling and apoptosis. Studies also show a significant correlation of high STAT1 activity with longer colorectal cancer patient overall survival. Recent studies have shown that STAT1 suppresses mouse mammary gland tumorigenesis by immune regulatory as well as tumor cell-specific functions of STAT1.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 341942077 273 FLVEKQP--------PQVLKTQTKFQAGVRFLLGLQFLGTSAKPPMVRADMVTEKQA----RELSLaqgpgtgVESTGEI 340
Cdd:cd16845    1 FVVERQPcmpthpqrPLVLKTGVQFTVKLRLLVKLQELNYQLKVKVLFDKDVTEKNTvkgfRKFNI-------LGTNTKV 73

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 341942077 341 MNntvpLENSiPSNCCSALFKNLLLKKIKRCERKGTES---VTEEKCAVLFSTSFTlgPNKLLIQLQALSLPLVVIVHGN 417
Cdd:cd16845   74 MN----MEES-TNGSLAAEFRHLQLKEQKNAGTRTNEGpliVTEELHSLSFETQLC--QPGLVIDLETTSLPIVVISNVS 146

                        170
                 ....*....|...
gi 341942077 418 QDNNAKATILWDN 430
Cdd:cd16845  147 QLPSGWASILWYN 159

Src homology 2 domains; Src homology 2 domains bind phosphotyrosine-containing polypeptides via 2 surface pockets. Specificity is provided via interaction with residues that are distinct from the phosphotyrosine. Only a single occurrence of a SH2 domain has been found in S. cerevisiae.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 341942077   540 GFISKQYVTSLLLNEPDGTFLLRFSDSEIGGITIAHVIRGqdgssQIENIQPFSAKDlSIRSLGDRIR--DLAQLKNLYP 617
Cdd:smart00252   6 GFISREEAEKLLKNEGDGDFLVRDSESSPGDYVLSVRVKG-----KVKHYRIRRNED-GKFYLEGGRKfpSLVELVEHYQ 79

                   ...
gi 341942077   618 KKP 620
Cdd:smart00252  80 KNS 82

STAT protein, all-alpha domain; STAT proteins (Signal Transducers and Activators of Transcription) are a family of transcription factors that are specifically activated to regulate gene transcription when cells encounter cytokines and growth factors. STAT proteins also include an SH2 domain pfam00017.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 341942077  178 DLATMLQGTVGDLEATQALVL--KRIQiWKRQQQLAGNGTPFEESLAGLQERCESLVEIYSQLQQEI 242
Cdd:pfam01017  70 EVLDKLKELLNLLETLQELLLdeELIE-WKRRQQLACIGAPPNACLDQLQNWFTALAESLWQLRQQL 135

DNA-binding domain of Signal Transducer and Activator of Transcription 3 (STAT3); This family consists of the DNA-binding domain (DBD) of the STAT3 proteins (Signal Transducer and Activator of Transcription 3, or Signal Transduction And Transcription 3). The DNA binding domain has an Ig-like fold. STAT3 plays key roles in vertebrate development and mature tissue function including control of inflammation and immunity. Mutations in human STAT3, especially in the DNA-binding and SH2 domains, are associated with diseases such as autoimmunity, immunodeficiency and cancer. STAT3 regulation is tightly controlled since either inactivation or hyperactivation results in disease. STAT3 activation is stimulated by several cytokines and growth factors, via diverse receptors. For example, IL-6 receptors depend on the tyrosine kinases JAK1 or JAK2, which associate with the cytoplasmic tail of gp130, and results in STAT3 phosphorylation, dimerization, and translocation to the nucleus; this leads to further IL-6 production and up-regulation of anti-apoptotic genes, thus promoting various cellular processes required for cancer progression. Other activators of STAT3 include IL-10, IL-23, and LPS activation of Toll-like receptors TLR4 and TLR9. STAT3 is constitutively activated in numerous cancer types, including over 40% of breast cancers. It has been shown to play a significant role in promoting acute myeloid leukemia (AML) through three mechanisms: promoting proliferation and survival, preventing AML differentiation to functional dendritic cells (DCs), and blocking T-cell function through other pathways. STAT3 also regulates mitochondrion functions, as well as gene expression through epigenetic mechanisms; its activation is induced by overexpression of Bcl-2 via an increase in mitochondrial superoxide. Thus, many of the regulators and functions of JAK-STAT3 in tumors are important therapeutic targets for cancer treatment.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 341942077 273 FLVEKQP--------PQVLKTQTKFQAGVRFLLGLQFLGTSAKppmvrADMVTEKQARELSLAQGpgtgvESTGEIMNNT 344
Cdd:cd16847    1 FVVERQPcmpmhpdrPLVIKTGVQFTTKVRLLVKFPELNYQLK-----IKVCIDKDSGDVAALRG-----SRKFNILGTN 70

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 341942077 345 VPLENSIPSN--CCSALFKNLLLKKiKRCERKGTES------VTEEKCAVLFSTSftLGPNKLLIQLQALSLPLVVIVHG 416
Cdd:cd16847   71 TKVMNMEESNngSLSAEFKHLTLRE-QRCGNGGRANcdasliVTEELHLITFETE--VYHQGLKIDLETHSLPVVVISNI 147

                        170
                 ....*....|....*..
gi 341942077 417 NQDNNAKATILWDNAFS 433
Cdd:cd16847  148 CQMPNAWASILWYNMLT 164

Src homology 2 domain found in the SH2 domain containing protein 2A and 7 (SH2D2A and SH2D7); SH2D2A and SH7 both contain a single SH2 domain. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|..
gi 341942077 540 GFISKQYVTSLLLNEPDGTFLLRFSDSEIGGITiahVIRGQD 581
Cdd:cd10349    5 GFITRREAERLLEPKPQGCYLVRFSESAVTFVL---SYRSRT 43